PROJECT SUMMARY The United States is in the midst of a serious opioid epidemic. Nearly 2 million adults have an opioid use disorder (OUD) and there has been a rapidly increasing rate of opioid overdose deaths. Prescription opioids are considered a major contributor to the opioid epidemic, and are frequently an antecedent to the use of illicit opioids, such as heroin. More than 200 million prescription opioids are dispensed each year in the U.S., and are frequently given to relieve pain among patients recovering from surgery. New methods of pain management are needed to reduce or eliminate the reliance on prescription opioids. This K01 application will prepare the candidate to pursue a career devoted to understanding and harnessing the placebo response in opioid and other substance misuse prevention and treatment. The candidate is very well suited for this career given his strong background in alcohol prevention and emerging expertise in placebo studies. The research plan will entail a two-phase project to develop and test open (i.e. ?honest?) placebos as an adjunctive treatment for pain management in post-surgical patients. Although harnessing placebos for substance misuse prevention has never been studied, the proposed research and career trajectory build upon an emerging body of evidence showing that placebos relieve pain, and that placebos are effective even when given openly. Phase 1 will consist of qualitative interviews with patients (n=15-20) and physicians (n=5-7) to determine how open placebos can be adapted to a post-surgical pain population (Aim 1). Phase 2 will consist of a randomized clinical trial (n=155). Patients recovering from Carpal Tunnel Release Surgery will be assigned to one of two groups. Patients in both standard care (SC) and placebo conditioning (PC) will receive their usual dose of opioid medication for post-surgical pain. Patients assigned to the PC group will also receive a set regimen of placebos. The pills will be truthfully described as inactive medication that is likely to minimize pain. They will be asked to take placebos in a manner that generates a Pavlovian conditioned analgesic response to the placebos. Opioid intake and pain will be assessed over the course of seven daily follow-ups. Aims 2 and 3 will examine whether patients in the PC group take fewer active opioid pills (Aim 2) and report less pain (Aim 3) than patients assigned to SC. Aim 4 will examine whether treatment expectancies mediate the treatment effect. This project is in line with the NIDA funding priority of developing non-opioid adjunctive therapies for prescription opioid misuse prevention. A well-designed career plan and exceptional mentorship team will prepare the candidate to develop expertise in: a) pain management, opioid misuse and use disorder prevention and treatment, b) placebo studies, c) formative intervention development, and d) advanced quantitative methods. At the conclusion of this K01, the candidate will be a leading expert on the application of placebo research to opioid and other substance misuse prevention and treatment. He will be prepared to launch an independent, grant-supported career in this novel and highly promising area.